31 May 20211 EMA/PRAC/250777/2021 Corr 2 Pharmacovigilance Risk Assessment Committee (PRAC) PRAC recommendations on signals Adopted at the 3-6 May 2021 PRAC meeting This document provides an overview of the recommendations adopted by the Pharmacovigilance Risk Assessment Committee (PRAC) on the signals discussed during the meeting of 3-6 May 2021 (including the signal European Pharmacovigilance Issues Tracking Tool [EPITT]3 reference numbers). PRAC recommendations to provide supplementary information are directly actionable by the concerned marketing authorisation holders (MAHs). PRAC recommendations for regulatory action (e.g. amendment of the product information) are submitted to the Committee for Medicinal Products for Human Use (CHMP) for endorsement when the signal concerns Centrally Authorised Products (CAPs), and to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for information in the case of Nationally Authorised Products (NAPs). Thereafter, MAHs are expected to take action according to the PRAC recommendations. When appropriate, the PRAC may also recommend the conduct of additional analyses by the Agency or Member States. MAHs are reminded that in line with Article 16(3) of Regulation No (EU) 726/2004 and Article 23(3) of Directive 2001/83/EC, they shall ensure that their product information is kept up to date with the current scientific knowledge including the conclusions of the assessment and recommendations published on the European Medicines Agency (EMA) website (currently acting as the EU medicines webportal). For CAPs, at the time of publication, PRAC recommendations for update of product information have been agreed by the CHMP at their plenary meeting (17-20 May 2021) and corresponding variations will be assessed by the CHMP. For nationally authorised medicinal products, it is the responsibility of the National Competent Authorities (NCAs) of the Member States to oversee that PRAC recommendations on signals are adhered to. 1 Expected publication date. The actual publication date can be checked on the webpage dedicated to PRAC recommendations on safety signals. 2 Section 4.4 of the summary of product characteristics for clindamycin was revised by PRAC on 22 July 2021 (see page 5). 3 The relevant EPITT reference number should be used in any communication related to a signal. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. Variations for CAPs are handled according to established EMA procedures. MAHs are referred to the available guidance. Variations for NAPs (including via mutual recognition and decentralised procedures) are handled at national level in accordance with the provisions of the Member States. The timeline recommended by PRAC for submission of variations following signal assessment is applicable to both innovator and generic medicinal products, unless otherwise specified. For procedural aspects related to the handling of PRAC recommendations on signals (e.g. submission requirements, contact points, etc.) please refer to the Questions and Answers on signal management. PRAC recommendations on signals EMA/PRAC/250777/2021 Page 2/15 4 1. Recommendations for update of the product information 1.1. Alemtuzumab – Sarcoidosis Authorisation procedure Centralised EPITT No 19638 PRAC rapporteur(s) Anette Kirstine Stark (DK) Date of adoption 6 May 2021 Recommendation The PRAC has considered available evidence ascertained from EudraVigilance, the literature, nonclinical and clinical data and additional data submitted by Sanofi Belgium. Based on review of the weighted cumulative evidence, PRAC considers that a causal relation between Sarcoidosis and Alemtuzumab cannot be excluded. The PRAC recommends that the MAH for Lemtrada, Sanofi Belgium, should submit a variation within 2 months from the publication of the PRAC recommendation, to amend the product information as described below (new text underlined): The proposal to update the SmPC and PIL is as follows (new text underlined, text to be removed struck-through). Summary of product characteristics 4.4. Special warnings and precautions for use Autoimmunity Treatment may result in the formation of autoantibodies and increase the risk of autoimmune mediated conditions which may be serious and life threatening. Reported autoimmune conditions, include thyroid disorders, immune thrombocytopenic purpura (ITP), nephropathies (e.g. anti- glomerular basement membrane disease), autoimmune hepatitis (AIH), and acquired haemophilia A, and sarcoidosis. In the post-marketing setting, patients developing multiple autoimmune disorders after LEMTRADA treatment have been observed. Patients who develop autoimmunity should be assessed for other autoimmune mediated conditions (see section 4.3). Patients and physicians should be made aware of the potential later onset of autoimmune disorders after the 48 months monitoring period. […] 4.8. Undesirable effects SOC: Immune system disorders Frequency uncommon: Sarcoidosis Package leaflet 2. What you need to know before you are administered LEMTRADA […] • Autoimmune conditions 4 Translations in all official EU languages of the new product information adopted by PRAC are also available to MAHs on the EMA website. PRAC recommendations on signals EMA/PRAC/250777/2021 Page 3/15 […] More helpful information about these autoimmune conditions (and the testing for them) can be found in the LEMTRADA Patient Guide. […] o Liver inflammation Some patients have developed liver inflammation after receiving LEMTRADA. Liver inflammation can be diagnosed from the blood tests that you will be having regularly after LEMTRADA treatment. If you develop one or more of the following symptoms report this to your doctor: nausea, vomiting, abdominal pain, fatigue, loss of appetite, yellow skin or eyes, dark urine, or bleeding or bruising more easily than normal. o Sarcoidosis There have been reports of an immune system disorder (sarcoidosis) in patients treated with LEMTRADA. Symptoms can include persistent dry cough, shortness of breath, chest pain, fever, lymph node swelling, weight loss, skin rashes, and blurred vision. o Other autoimmune conditions Uncommonly, patients have experienced autoimmune conditions involving red blood cells or white blood cells. These can be diagnosed from the blood tests that you will be having regularly after LEMTRADA treatment. If you develop one of these conditions your doctor will tell you, and take appropriate measures to treat it. […] 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. The most important side effects are the autoimmune conditions described in section 2 which include: […] • Thyroid disorders (very common – may affect more than 1 in 10 people): may show as excessive sweating; unexplained weight-loss or gain; eye swelling; nervousness; fast heartbeat; feeling cold; worsening tiredness; or newly occurring constipation. • Red and white blood cells disorders (uncommon – may affect up to 1 in 100 people): diagnosed from your blood tests. • Sarcoidosis (uncommon – may affect up to 1 in 100 people): Symptoms can include persistent dry cough, shortness of breath, chest pain, fever, lymph node swelling, weight loss, skin rashes, and blurred vision. […] These are the side effects that you may experience: Uncommon (may affect up to 1 in 100 people) PRAC recommendations on signals EMA/PRAC/250777/2021 Page 4/15 • Sarcoidosis • […] 1.2. Clindamycin – Acute renal failure Authorisation procedure Non-centralised EPITT No 19647 PRAC rapporteur(s) Sonja Hrabcik (AT) Date of adoption 6 May 2021 Recommendation Having considered the available evidence in EudraVigilance, the literature, and the data submitted by Pfizer the PRAC has agreed that the MAH(s) of clindamycin-containing medicinal products for systemic use should submit a variation within 2 months, to amend the product information as described below (new text underlined): Summary of product characteristics 4.4. Special warnings and precautions for use5 If therapy is prolonged, liver and kidney functions tests should be performed. Acute kidney injury, including acute renal failure, has been reported infrequently. In patients suffering from pre-existing renal dysfunction or taking concomitant nephrotoxic drugs, monitoring of renal function should be considered (see section 4.8). 4.8. Undesirable effects Renal and urinary disorders Frequency ‘not known’: Acute kidney injury# # See section 4.4 Package leaflet 2. What you need to know before you take <product name> Warnings and precautions Acute kidney disorders may occur. Please inform your doctor about any medication you currently take and if you have any existing problems with your kidneys. If you experience decreased urine output, fluid retention causing swelling in your legs, ankles or feet, shortness of breath, or nausea you should contact your doctor immediately. 4. Possible side effects Tell your doctor immediately if you develop: • fluid retention causing swelling in your legs, ankles or feet, shortness of breath or nausea 5 Section 4.4 was revised by PRAC on 22 July 2021. PRAC recommendations on signals EMA/PRAC/250777/2021 Page 5/15 1.3. COVID-19 mRNA6 vaccine (nucleoside-modified) – Comirnaty